Cell Stem Cell
In Translation
Cellular Transplantation into Lymph NodesMay Not Be Such a Crazy Idea
Gordon C. Weir1,2,*1Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA2Department of Medicine, Harvard Medical School, Boston, MA 02115, USA*Correspondence: [email protected]://dx.doi.org/10.1016/j.stem.2012.10.004
A study published in Nature Biotechnology by Komori and colleagues (Komori et al., 2012) has identifiedthe surprising potential of lymph nodes as sites for cellular transplants.
Amidst the excitement about the future
of cellular transplants, there are uncer-
tainties about where these cells should
be placed. For example, there are obsta-
cles to transplanting hepatocytes into a
diseased liver or islets into the pancreas
of individuals with diabetes. In their recent
study, Komori et al. explore the novel idea
that lymph nodes have characteristics
that make them potentially useful sites
for transplantation. Transplantation of
hepatocytes, thymus tissue, and pancre-
atic islets were found to have therapeutic
effects for hepatic failure, thymus agen-
esis, and diabetes in mice. While many
sites in the body have been explored as
transplant sites, little attention has been
paid to lymph nodes, probably due to
the assumption that they would be
immunologically hostile and too small
to accommodate transplanted tissue.
However, the authors were intrigued by
the ability of cancer cells to migrate to
lymph nodes where they seem to grow
and thrive, and wondered if nonmalignant
cells would do the same. They also
pointed out that lymph nodes are numer-
ous and accessible, properties on which
they aimed to capitalize.
The prospect of treating liver disease
with transplantation of hepatocytes has
been bolstered by the great success
of liver whole-organ transplantation. In
this study syngeneic mouse hepatocytes
marked with green fluorescent protein
were injected into the single large jejunal
lymph node, where they were retained
in the subcapsular sinus rather than the
follicles or germinal centers. The hepato-
cytes then formed patches of cells ex-
pressing E-cadherin accompanied by
remodeling of blood vessels and sub-
stantial growth, which could be further
stimulated by partial hepatectomy.
This growth potential was then studied
in a mouse model of hepatic failure, an
experimental version of tyrosinemia type
1 caused by deficiency of fumarylacetoa-
cetate hydrolase (Fah�/�) (Grompe et al.,
1995). Isolated hepatocytes, 100,000–
500,000 in number with an estimated
weight of 4–40 mg, were transplanted
into the jejunal lymph node weighing
about 25 mg. At some point more than
10 weeks after transplantation the weight
of such lymph nodes had expanded to
about 800 mg. The authors estimated
that the hepatocytes in one lymph node
grew to ‘‘around 70% of the liver mass.’’
Most importantly, these transplanted cells
rescued the mice from fatal metabolic
liver failure. To further explore therapeutic
potential, transplants were performed
with allogenic hepatocytes that could
engraft successfully in Fah�/� mice as
long as the recipients were immunosup-
pressed by the blocking of costimulation
from the immune-stimulating pathways
controlled by CD28-B7 and CD40-
CD40L signaling. These findings provide
hope that this new approach to hepato-
cyte transplantation will someday help
people with liver insufficiency.
The challenge of creating a functional
ectopic thymus in lymph nodes was also
undertaken using this method. In athymic
children with complete DiGeorge syn-
drome, thymus tissue has been trans-
planted into the quadriceps with generally
poor results, thought to result from using
a suboptimal transplant site (Rice et al.,
2004).
Another remarkable finding reported
by Komori et al. was the development of
thymus function from minced pieces
of thymus gland transplanted into jejunal
lymph nodes of athymic mice. One
month after the transplant, circulating
Cell Stem Cell 11,
single-positive CD4+ and CD8+ recipient
T cells were present, and they could still
be found 10 months later, suggesting
long-term function of the graft. Genetic
analyses of T cell receptors on the newly
generated T cells provided assurance
that they were derived from the recipient’s
bone marrow. Evidence for function of
this ectopic thymus tissue came from
rejection of allogenic skin grafts and
xenogeneic tumor cells, demonstrating
that a newly acquired T cell-dependent
immunity had been acquired in transplant
recipients.
For many years diabetes has been
considered a particularly attractive target
for cellular therapy. This has been rein-
forced by the critical proof-of-principle
success of human islet transplantation.
Since 1990, it has been possible for
someone with type 1 diabetes to undergo
a relatively minor surgical or radiological
procedure to have human islets intro-
duced into the portal vein, which then
lodge in the liver and can normalize
glucose levels in some patients for as
long as 10 years (Harlan et al., 2009).
There are complexities and safety con-
cerns that prevent widespread use of
this current approach, but scientists
are working feverishly to find a better
source of beta-cells and to prevent
their destruction from allorejection and
autoimmunity.
Much has been done to identify the
optimal extrapanceatic site for trans-
planted islets. Work in experimental
animals indicates that islets can be trans-
planted almost anywhere and reverse
hyperglycemia. Success has been found
with the following sites: liver; spleen; renal
subcapsular space; peritoneum; omen-
tal pouch; gastric, intestinal, and rectal
mucosa; subcutaneous; bone marrow;
November 2, 2012 ª2012 Elsevier Inc. 587
Cell Stem Cell
In Translation
testes; brain; the anterior chamber of the
eye; lung; and probably others. There
are data suggesting that transplanting
islets back into the pancreas might be
possible (Lau et al., 2009), but fear of
pancreatitis has made this option less
attractive. The possibility of using lymph
nodes is raised by the current study.
Indeed, the authors transplanted 200–
300 mouse islets mixed with Matrigel
into a jejunal lymph node and reversed
streptozocin diabetes. Interestingly, like
the transplanted hepatocytes, the islet
cells were found to be localized in the
subcapsular sinus of the lymph nodes.
Unfortunately, information about b cell
mass and growth was not provided.
Because of the impressive growth of
hepatocytes in lymph nodes, it will be
important to determine what happens to
islet cells in a lymph node compared to
those in hepatic and renal capsular sites
with regard to b cell mass, proliferation,
and apoptosis, as well as the pattern of
vascularization (Henriksnas et al., 2012),
and the topographical relationship among
the different islet cell types (King et al.,
2007). Until such studies are done, there
is no compelling reason to think that islet
function and survival will be better in
lymph nodes than in other sites. Because
of concerns that islet cells in a lymph
node might be more susceptible to
588 Cell Stem Cell 11, November 2, 2012 ª2
immune killing, an inflammation reac-
tion in islet transplant recipients was
induced with an injection of lipopoly-
saccharide (LPS, a highly immunostimu-
latory bacterial antigen), which resulted
in increased serum levels of inflammatory
cytokines such as tumor necrosis factor-
a, interleukin-1b, and interleukin-6. This
did not lead to destruction of the grafts
as evidenced by maintenance of
normoglycemia.
The lymph node site may have some
other advantages. Their accessibility is
attractive as the next generation of islet
cells, such as those generated from
embryonic stem cells or induced pluripo-
tent cells, is evaluated (Kroon et al.,
2008). This accessibility should make it
possible to monitor cells by biopsy or
excision to determine safety, changes in
islet cell mass and morphology, and the
presence and behavior of immune cells.
Another potential advantage is that islets
injected by laparoscopy into intestinal
lymph nodes would secrete their insulin
and glucagon into the portal vein, as nor-
mally happens with islets in the pancreas.
Such drainage directly into the liver is
more physiological, which might lead to
better hepatic metabolic function and
less peripheral hyperinsulinemia, which
has been postulated to have proathero-
genic effects.
012 Elsevier Inc.
This provocative study raises important
questions about lymph nodes as a hith-
erto-ignored site for cellular transplanta-
tion. We eagerly await further exploration
into how this novel transplant site might
be used for clinical application.
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